Prenatal human skin morphogenesis is regulated by crosstalk between immune and non-immune cells

The prenatal human skin is populated by innate immune cells, including macrophages, very early during skin development. However, the role of macrophages if any during early skin morphogenesis is uncertain. We assembled a single cell multi-omic and spatial transcriptomics reference atlas of prenatal human skin from 7-16 post-conception weeks which unravelled microenvironmental cellular organisation and cross-talk between non-immune and immune cells that underpinned hair-follicle formation and skin vascular network formation. We benchmarked a human ES/iPS-derived skin organoid model against prenatal and adult skin that demonstrated close recapitulation of the epithelial and mesenchymal components during hair follicle development. However, the skin organoid was absent in immune cells and had markedly diminished endothelial cell heterogeneity and frequency. We predicted key requirements for macrophages and macrophage-derived growth factors in driving vascular network formation in human prenatal skin and functionally validated the enhancement in vascular network development following transfer of autologous iPS-derived macrophages into an endothelial cell angiogenesis assay and skin organoid cultures.